The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery

Background: Proinflammatory (M1) macrophages and anti-inflammatory (M2) macrophages have been identified in atherosclerotic plaques. While these macrophages have been speculated to be related to plaque vulnerability, there are limited studies investigating this relationship. Therefore, we examined the association between macrophage phenotype (M1 versus M2) and plaque vulnerability and clinical events. Methods: Patients undergoing carotid endarterectomy received an ultrasound of the carotid artery before surgery. Plaques were processed for analysis by immunohistochemistry, Western blotting, and real-time polymerase chain reaction studies. Medical history and clinical data were obtained from medical records. Results: Patients were divided into 2 groups: those suffering from acute ischemic attack (symptomatic, n = 31) and those that did not present with symptoms (asymptomatic, n = 34). Ultrasound analysis revealed that plaque vulnerability was greater in the symptomatic group (P= .033; Chi-square test). Immunohistochemistry revealed that plaques from the symptomatic group had a greater concentration of M1 macrophages (CD68-, CD11c-positive) while plaques from the asymptomatic group had more M2 macrophages (CD163-positive). This observation was confirmed by Western blotting. Characterization by real-time polymerase chain reaction studies revealed that plaques from the symptomatic group had increased expression of the M1 markers CD68 and CD11c, as well as monocyte chemoattractive protein-1, interleukin-6, and matrix metalloproteinase-9. In addition, more M1 macrophages expressed in unstable plaques were defined by ultrasound analysis, while more M2 macrophages were expressed in stable plaques. Conclusions: Our data show that M1 macrophage content of atherosclerotic plaques is associated with clinical incidence of ischemic stroke and increased inflammation or fibrinolysis. We also show the benefits of using ultrasound to evaluate vulnerability in the plaques

Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis

The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-α) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance

Embedded DRAM using c-axis-aligned crystalline In-Ga-Zn oxide FET with 1.8V-power-supply voltage

An embedded memory using c-axis aligned crystalline In-Ga-Zn oxide (CAAC-IGZO) FETs with an extremely low off-state current on the order of yoctoamperes (yA) (yocto- is a metric prefix denoting a factor of 10-24) is known as a potential next-generation memory [1][2]. A dynamic oxide semiconductor RAM (DOSRAM), where each memory cell is composed of one CAAC-IGZO FET and one capacitor, enables long data retention and long interval of refresh operations with an advantage of extremely low off-state current of the CAAC-IGZO FET. However, negative backgate voltage (Vbg) and word-line driving voltages of 0/3.3 V (VSSL/VDDH) had been required for an access transistor of the memory cell to satisfy high on-state current and low off-state current. This work shows that DOSRAM operates with 1.8 V-power supply voltage by using a novel driving method. Figure 1 shows Vg-Id performance of a CAAC-IGZO FET used as a cell transistor. The threshold voltage (Vth) of the CAAC-IGZO FET is controlled by changing a level of Vbg, whereas Vth of the Si FET is controlled by channel doping. Figure 2 shows a block diagram of a prototyped DOSRAM. The refresh rate in DOSRAM mainly depends on the leakage current of cell transistors. To reduce the refresh rate to once an hour, the off-state current of the cell transistors on a non-selected word line needs to be reduced to 200 zeptoamperes (zA) per FET (zepto- is a metric prefix denoting a factor of 10-21) or lower at 85C. The required Vbg is -7.0 V to achieve such an off-state current at Vg 0 V, for example. To obtain approx. 100 MHz-driving frequency, the required on-state current is at least several microamperes. The voltage level difference in the word line, VDDH VSSL, is a factor that determines the on-state current, and in this work is fixed to 3.3 V so that the combination of Vbg and the word line voltage is optimized. The application of negative voltage to the word line enables the leakage current of the cell transistor to be maintained low even when Vbg is increased. For example, whereas the existing driving method meets the above off-state current value with Vbg -7.0 V and the VSSL 0 V, the novel driving method meets the value with Vbg 0 V and VSSL -1.5 V. In the novel driving method, VDDH 1.8 V. There has been a report of a reduction in leakage current of a memory cell by application of negative voltage to a top gate in DRAM using Si CMOS [3]. In contrast to it, DOSRAM including CAAC-IGZO FETs with L 60 nm has a leakage current of 200 zA or lower, which is 7-digit lower than that of the DRAM using Si CMOS, and enables longer data retention. The evaluation results of the prototyped DOSRAM verify that a reduction in power-supply voltage from 3.3 V to 1.8 V is possible in terms of operation and data retention. This suggests a highly compatible and efficient configuration of an embedded DRAM and a logic circuit where signals can be transmitted with low VDD. References [1] S. H. Wu, et al., IEEE Symp. VLSI Tech., pp. 166-167, 2017. [2] T. Ishizu, et al., IEEE Symp. VLSI Cir., pp. 162-163, 2017. [3] F. Hamzaoglu et al., IEEE Journal of Solid-State Circuits, vol. 50, no. 1, pp. 150-157, Jan. 2015

Pregnancy outcomes in antiphospholipid antibody positive patients: prospective results from the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ('Registry').

Objectives: To describe the outcomes of pregnancies in antiphospholipid antibody (aPL)-positive patients since the inception of the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Registry. Methods: We identified persistently aPL-positive patients recorded as 'pregnant' during prospective follow-up, and defined 'aPL-related outcome' as a composite of: (1) Preterm live delivery (PTLD) at or before 37th week due to pre-eclampsia (PEC), eclampsia, small-for-gestational age (SGA) and/or placental insufficiency (PI); or (2) Otherwise unexplained fetal death after the 10th week of gestation. The primary objective was to describe the characteristics of patients with and without aPL-related composite outcomes based on their first observed pregnancies following registry recruitment. Results: Of the 55 first pregnancies observed after registry recruitment among nulliparous and multiparous participants, 15 (27%) resulted in early pregnancy loss <10 weeks gestation. Of the remaining 40 pregnancies: (1) 26 (65%) resulted in term live delivery (TLD), 4 (10%) in PTLD between 34.0 weeks and 36.6 weeks, 5 (12.5%) in PTLD before 34th week, and 5 (12.5%) in fetal death (two associated with genetic anomalies); and (2) The aPL-related composite outcome occurred in 9 (23%). One of 26 (4%) pregnancies with TLD, 3/4 (75%) with PTLD between 34.0 weeks and 36.6 weeks, and 3/5 (60%) with PTLD before 34th week were complicated with PEC, SGA and/or PI. Fifty of 55 (91%) pregnancies were in lupus anticoagulant positive subjects, as well as all pregnancies with aPL-related composite outcome. Conclusion: In our multicentre, international, aPL-positive cohort, of 55 first pregnancies observed prospectively, 15 (27%) were complicated by early pregnancy loss. Of the remaining 40 pregnancies, composite pregnancy morbidity was observed in 9 (23%) pregnancies

Exploratory classification of clinical phenotypes in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis using cluster analysis

A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n=8) and proteinase 3-ANCA-positive (n=41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n=47); cutaneous (n=36); renal (n=256), non-renal (n=33); and both ENT and cutaneous symptoms (n=6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n=42), without s-Cr elevation (1.3 mg/dL) with high CRP (>10 mg/dL) (n=71), or s-Cr elevation (>= 1.3 mg/dL) without high CRP (<= 10 mg/dL) (n=157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis

The adjusted global antiphospholipid syndrome score (aGAPSS) and the risk of recurrent thrombosis: Results from the APS ACTION cohort

Objectives: To assess whether patients with antiphospholipid syndrome (APS) and history of recurrent thrombosis have higher levels of adjusted Global AntiphosPholipid Syndrome Score (aGAPSS) when compared to patients without recurrent thrombosis. Methods: In this cross-sectional study of antiphospholipid antibody (aPL)-positive patients, we identified APS patients with a history of documented thrombosis from the AntiPhospholipid Syndrome Alliance For Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository (“Registry”). Data on aPL-related medical history and cardiovascular risk factors were retrospectively collected. The aGAPSS was calculated at Registry entry by adding the points corresponding to the risk factors: three for hyperlipidemia, one for arterial hypertension, five for positive anticardiolipin antibodies, four for positive anti-β2 glycoprotein-I antibodies and four for positive lupus anticoagulant test. Results: The analysis included 379 APS patients who presented with arterial and/or venous thrombosis. Overall, significantly higher aGAPSS were seen in patients with recurrent thrombosis (arterial or venous) compared to those without recurrence (7.8 ± 3.3 vs. 6 ± 3.9, p<0.05). When analyzed based on the site of the recurrence, patients with recurrent arterial, but not venous, thrombosis had higher aGAPSS (8.1 ± SD 2.9 vs. 6 ± 3.9; p<0.05). Conclusions: Based on analysis of our international large-scale Registry of aPL-positive patients, the aGAPSS might help risk stratifying patients based on the likelihood of developing recurrent thrombosis in APS

Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study

OBJECTIVE: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. RESULTS: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. CONCLUSIONS: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009

Coulomb breakup reactions of 93,94 Zr in inverse kinematics

Coulomb breakup reactions of 93,94 Zr have been studied in inverse kinematics at incident beam energies of about 200 MeV/nucleon in order to evaluate neutron capture reaction methods. The 93 Zr(n,γ) 94 Zr reaction is particularly important as a candidate nuclear transmutation reaction for the long-lived fission product 93 Zr in nuclear power plants. One- and two-neutron removal cross sections on Pb and C targets were measured to deduce the inclusive Coulomb breakup cross sections, 375 ± 29 (stat.) ± 30 (syst.) and 403 ± 26 (stat.) ± 31 (syst.) mb for 93 Zr and 94 Zr, respectively. The results are compared with estimates using the standard Lorentzian model and microscopic calculations. The results reveal a possible contribution of the pygmy dipole resonance or giant quadrupole resonance in the Coulomb breakup reactions of 94 Zr

Neuropsychological assessment of visuo-perceptual processing in children with neurodevelopmental disorders

Rey 複雑図形検査（Rey-Osterrieth Complex Figure test）は視空間構成能力や視覚性記憶，実行機能などを評価する神経心理学的検査である。本研究では板書のノートテイクや漢字の書字などの学習場面でのつまずきがみられる３名の神経発達障害をともなう子どもを対象に Rey 複雑図形検査を実施し，視覚認知処理過程に関する検討をおこなった。３名はいずれもまとまりのある要素を細分化させた方略を用いて図形を描画しており，視覚構成能力に関する指標において著しい低値を認め，視知覚能力の発達の未成熟さが推測された。本検査は子どもの抱える学習上の問題の把握に有用であり，神経発達障害における視覚認知能力の発達的経過に関するさらなる検討が必要と考えられた。独立行政法人日本学術振興会　科研費（25870931